Nearly 80% of smokers attempting to quit, fail. While there is increased appreciation for genetic contributions to this statistic, the molecular mechanism(s) underlying this remain a critical gap in our knowledge. We have previously shown that multiple single-nucleotide polymorphisms (SNPs) across the Neuregulin 3 (NRG3) gene significantly associate with smoking cessation outcomes in two independent cohorts of smokers.104 We now have new evidence that SNPs previously identified to increase NRG3 expression are significantly associated with nicotine withdrawal phenotypes in smokers. Our published murine experiments104 demonstrate that this increased NRG3 expression may be responsible for affective nicotine withdrawal (WD) phenotypes in particular: (1) chronic nicotine and 24hWD increase mRNA and protein expression of NRG3 and it's receptor, ErbB4, in the ventral hippocampus, (2) genetic interruption of NRG3 signaling blocks expression of nicotine WD anxiety-like phenotypes in the Novelty-induced Hypophagia Test, a model shown to be dependent upon ventral hippocampal function, and (3) inhibition of ErbB4, the NRG3 receptor, by Afatinib reduced anxiety-like behaviors during WD in this same behavioral model.While this is persuasive evidence for the role of ventral hippocampal NRG3 signaling in modulating affective nicotine WD phenotypes, little is known regarding the precise mechanisms through which NRG3 and nicotine interact. Therefore, the overall goal of this proposal is to systematically investigate the cell-specific role of the NRG3- ErbB4 signaling in the ventral hippocampus during nicotine treatment and withdrawal. To accomplish this, we are posing three central questions: 1) Is NRG3-ErbB4 signaling between pyramidal cells and interneurons in the hippocampus necessary for expression of nicotine WD-induced anxiety?, 2) Does the location of nicotinic receptors and NRG3/ErB4 dictate chronic nicotine and 24hWD effects on cellular cascades and glutamatergic input?, and (3) How does nicotine-mediated NRG3-ErbB4 signaling regulate the activity of CCK+ and PV+ cells to influence the dynamic properties of the hippocampal circuit? Our approach is significant because it combines collective genetic information from both human and animal studies to generate a translational, high-impact hypothesis examining the functional role of this signaling pathway within the specific cell-types of the hippocampus during nicotine and withdrawal. Completion of these studies will expand understanding of the complex interplay between genetics, circuit function, and behavior in order to develop better, more specific smoking cessation aids.